1. Field of the Invention
This invention relates to substituted phenoxy acetic acids and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of chronic complications arising from diabetes mellitus.
2. Description of the Related Art
The use of aldose reductase inhibitors (ARIs) for the treatment of chronic diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD+ ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.
The use of aldose reductase inhibitors for the treatment of chronic diabetic complications has been extensively reviewed, see: (a) Textbook of Diabetes, 2nd ed.; Pickup, J. C. and Williams, G. (Eds.); Blackwell Science, Boston, Mass. 1997.; (b) Larson, E. R.; Lipinski, C. A. and Sarges, R., Medicinal Research Reviews, 1988, 8 (2), 159-198; (c) Dvornik, D. Aldose Reductase Inhibition. Porte, D. (ed), Biomedical Information Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M., Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes, Aldose Reductase Catalysis and Crystalography: Insights From Recent Advances in Enzyme Structure and Function, Diabetes, 1994, 43, 955; (e) Aotsuka, T.; Abe, N.; Fukushima, K.; Ashizawa, N. and Yoshida, M., Bioorg. and Med. Chem. Letters, 1997, 7, 1677, (f), T., Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K., J. Med. Chem., 1997, 40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.; Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A, Jpn. J. Pharmacol. 1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E., Molecular Pharmacology, 1983, 24, 521; (I) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E., J. Med. Chem. 1985, 28 (7), 841; (j) Hotta, N., Biomed. and Pharmacother. 1995, 5, 232; (k) Mylar, B.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T. W.; Singleton, D. H., J. Med. Chem. 1991, 34, 108; (l) Dvornik, D. Croatica Chemica Acta 1996, 69 (2), 613.
The following patents disclose compounds said to have activity as aldose reductase inhibitors: U.S. Pat. Nos. 5,700,819; 4,868,301; and 4,734,419. Although many aldose reductase inhibitors have been extensively developed, none have demonstrated sufficient efficacy in human clinical trials without significant undesirable side effects. Thus no aldose reductase inhibitors are currently available as approved therapeutic agents in the United States, and consequently, there is still a significant need for new, efficacious and safe medications for the treatment of diabetic complications.
This invention provides compounds that interact with and inhibit aldose reductase. Thus, in a broad aspect, the invention provides compounds of Formula I: 
or pharmaceutically acceptable salts thereof wherein
A is a covalent bond, C1-C4 alkylene group optionally substituted with C1-C2 alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro;
X is oxygen, sulfur or NR6, wherein each R6 is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
R1, R2, R3 and R4 are each independently
hydrogen, halogen, nitro, or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
OR7, SR7, S(O)R7, S(O)2R7, C(O)N(R7)2, or N(R7)2, wherein each R7 is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; or
a group of the formula 
xe2x80x83where
J is a bond, CH2, oxygen, or nitrogen; and
each r is independently 2 or 3;
R5 is hydroxy or a prodrug group; and
Ar represents aryl or heteroaryl, each of which is optionally substituted with up to five groups.
In another aspect, the invention provides methods for preparing such compounds.
The compounds of the invention inhibit aldose reductase. Since aldose reductase is critical to the production of high levels of sorbitol in individuals with diabetes, inhibitors of aldose reductase are useful in preventing and/or treating various complications associated with diabetes. The compounds of the invention are therefore effective for the treatment of diabetic complications as a result of their ability to inhibit aldose reductase.
Thus, in another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, nephropathy, and neuropathy.
In another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, keratopathy, wound healing, diabetic uveitis, diabetic cardiomyopathy, nephropathy, and neuropathy.
The compounds of the invention promote healing of wounds in mammals. In preferred aspects, the compounds are useful in promoting wound healing in diabetic mammals. Thus, the compounds of the invention may be employed in the treatment of wounds in mammals, preferably humans, more preferably in diabetic humans.
In still another aspect, the invention provides for the use of a compound or compounds of Formula I for the preparation of a medicament for the treatment of any of the disorders or diseases (a) listed above or (b) connected with diabetic complications.
Prolonged administration of an ACE inhibitor at a therapeutically effective dose may be deleterious or give rise to side effects in certain patients, for example, it may lead to significant deterioration of renal function, induce hyperkalemia, neutropenia, angioneurotic oedema, rash or diarrhea or give rise to a dry cough. The present invention provides combination therapy comprising administration of a compound of Formula I together with a vasodilator, preferably an ACE inhibitor. Such administration decreases the likelihood of problems associated with administration of vasodilators such as ACE inhibitors that otherwise may result from administration of one of these agents alone. Furthermore, diabetic complications involve a complex mechanism or number of mechanisms, which initiate a cascade of biochemical alternations that in turn lead to structural changes. These may result in a diverse patient population. The present invention, therefore, provides the additional advantage that it allows tailoring of treatment to the needs of a particular patient population.
In this aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I and vasodilator, preferably an ACE inhibitor, together with a pharmaceutically acceptable carrier and/or diluent. In addition, the invention contemplates methods of treating diseases or disorders associated with elevated plasma levels of glucose, including complications associated with diabetes and hypertension and/or, congestive heart failure. These methods comprise administering an effective amount of a compound of Formula I in combination with a vasodilating compound, preferably an ACE inhibitor, to a patient in need of such treatment, e.g., a patient suffering from diabetes or hypertension or a patient likely to contract either of those diseases.
In a related aspect, the invention provides methods for the treatment, prevention or reversal of the development of disease conditions associated with impaired neuronal conduction velocity. These methods comprise administering to a patient suffering from or prone to develop such disease conditions an effective amount of a compound of Formula I together with an effective amount of a vasodilating compound, such as for example, an angiotensin converting enzyme inhibitor.
Further, the invention provides methods for the treatment or prevention of diabetic neuropathy comprising administering to a patient suffering from or prone to develop such complications an effective amount of a compound of Formula I.
In still another aspect, the invention provides pharmaceutical compositions containing compounds of Formula I.
In yet another aspect, the invention provides intermediates useful for preparing the compounds of Formula I as well as synthetic methods for making such compounds and intermediates.
The numbering system for the compounds of Formula I is as follows: 
As noted above, the invention provides novel substituted phenoxyacetic acids useful in treating and/or preventing complications associated with or arising from elevated levels of glucose in individuals suffering from diabetes mellitus. These compounds are represented by Formula I above.
In preferred compounds of Formula I, as well as in compounds of Formulas II and III, X is oxygen.
In compounds of Formula I, the aryl and heteroaryl groups represented by Ar include:
phenyl where
(i) the phenyl group is optionally substituted with up to 3 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR7, SR7, S(O)R7, S(O)2R7 or N(R7)2 wherein R7 is hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
(ii) the phenyl group is optionally monosubstituted as described above in (i) and disubstituted with a C1-C5 alkylene group forming a cycloalkyl ring fused to the phenyl where the C1-C5 alkylene group is optionally further mono- or disubstituted with hydroxy, halogen, C1-C2 alkyl, C1-C2 alkoxy, amino or mono- or di(C1-C2)alkyl amino and where the C1-C5 alkylene group optionally contains one or two hetero atoms selected from oxygen, nitrogen and sulfur; or
(iii) the phenyl group is optionally substituted with up to 3 groups as described above in (i) and further condensed with benzo where the benzo is optionally substituted with one or two of halogen, cyano, nitro, trifluoromethyl, perfluoroethyl, trifluoroacetyl, or (C1-C6)alkanoyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, trifluoromethoxy, trifluoromethylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl;
a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur, two nitrogens one of which may be replaced by oxygen or sulfur, or three nitrogens one of which may be replaced by oxygen or sulfur, said heterocyclic 5-membered ring substituted by one or two fluoro, chloro, (C1-C6)alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C1-C6)alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, trifluoromethoxy, trifluoromethylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C1-C6)alkoxy, or one or, preferably, two fluoro and one trifluoromethyl, or three fluoro, said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, bromo, (C1-C6)alkyl or (C1-C6)alkoxy;
a heterocyclic 6-membered ring having one to three nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur, said heterocyclic 6-membered ring substituted by one or two (C1-C6)alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo or trifluoromethylthio, or one or two of fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, (C1-C6)alkyl or (C1-C6)alkoxy;
said benzo-condensed heterocyclic 5-membered or 6-membered rings optionally substituted in the heterocyclic 5-membered or 6-membered ring by one of fluoro, chloro, bromo, methoxy, or trifluoromethyl;
oxazole or thiazole condensed with a 6-membered aromatic group containing one or two nitrogen atoms, with thiophene or with furane, each optionally substituted by one of fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl;
imidazolopyridine or triazolopyridine optionally substituted by one of trifluoromethyl, trifluoromethylthio, bromo, or C1-C6 alkoxy, or two of fluoro or chloro;
thienothiophene or thienofuran optionally substituted by one of fluoro, chloro or trifluoromethyl; thienotriazole optionally substituted by one of chloro or trifluoromethyl;
naphthothiazole; naphthoxazole; or thienoisothiazole.
The heterocyclic 5-membered and 6-membered rings are optionally monosubstituted as described above and may be further disubstituted with a C1-C5 alkylene group forming a cycloalkyl ring fused to the heterocyclic ring where the C1-C5 alkylene group is optionally further mono- or disubstituted with hydroxy, halogen, C1-C2 alkyl, C1-C2 alkoxy, amino or mono- or di(C1-C2)alkyl amino and where the C1-C5 alkylene group optionally contains one or two hetero atoms selected from oxygen, nitrogen and sulfur.
More specific compounds of the invention are those of Formula I wherein Ar is optionally substituted benzothiazolyl, benzoxazolyl, isoquinolyl, benzothiophen-yl, benzofuran-yl or benzimidazolyl, or substituted oxadiazolyl or indolyl. Other more specific compounds are of Formula I those wherein, A is a covalent bond or CH2, R5 is hydroxy, and each of R1-R4 are independently hydrogen, halogen, more preferably bromo, chloro or fluoro, C1-C6, more preferably, C1-C2 alkyl, phenoxy, benzyloxy, or C1-C6, more preferably, C1-C2 alkoxy. In the compounds of Formula I, R1 and R4 are more preferably hydrogen or C1-C3 alkyl, most preferably. hydrogen. Also, the more preferred compounds of Formula I are those where R2 and R3 are independently hydrogen, halogen, more preferably chloro or fluoro, C1-C6 alkyl, more preferably methyl or ethyl, C1-C6 alkoxy, more preferably methoxy or ethoxy, amino, mono or di(C1-C3)alkylamino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.
Preferred compounds of the invention are those wherein A is methylene, R5 is hydroxy, Ar is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl, benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl, benzothiophen-2-yl, benzofuran-2-yl, or thazolo[4,5-pyridine-2-y, thieno[2,3-b]pyridine2-yl, imidazo[1,5-a]pyridine-2-yl, or indol-2-yl, or substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isothiazol-5-yl, isothiazol-4-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl, or thiazol-4-yl, R1-R4 are independently hydrogen, halogen, more preferably bromo, chloro or fluoro, C1-C2 alkyl, phenoxy, benzyloxy or phenyl where each phenyl portion is optionally substituted with C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxy, amino or mono- or di (C1-C6) alkylamino. Preferably, R1 and R4 in the compounds of the invention are hydrogen or C1-C3 alkyl, more preferably hydrogen.
Other more specific compounds of the invention are those wherein A is methylene, R5 is hydroxy, Ar is optionally 4,5,6 or 7 benzo-substituted benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, or indolyl, or Ar is 2-benzothiazolyl substituted on benzo by one trifluoroacetyl or trifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or one or, preferably, two fluoro and one trifluoromethyl, or two fluoro or two trifluoromethyl with one methoxy, or three fluoro, or by 6,7-benzo. Preferably, R1 and R4 in the compounds of the invention are hydrogen or C1-C3 alkyl, more preferably hydrogen.
Preferred compounds of the invention include those where Ar in Formula I is substituted phenyl, i.e., compounds of Formula II: 
wherein
A is a C1-C4 alkylene group optionally substituted with C1-C2 alkyl;
X is oxygen, sulfur or NR6, wherein each R6 is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
R1, R2, R3 and R4 are each independently
hydrogen, halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR7, SR7, S(O)R7, S(O)2NR7, C(O)N(R7)2, or N(R7)2, wherein each R7 is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; or
a group of the formula 
xe2x80x83where
J is a bond, CH2, oxygen, or nitrogen; and
each r is independently 2, or 3;
R5 is hydroxy, an alkoxy group of 1-6 carbon atoms, or xe2x80x94Oxe2x80x94M+ where M+ is a cation forming a pharmaceutically acceptable salt; and
R8, R9, R10, R11, and R12 in combination, represent hydrogen, or 1-3 groups selected from fluorine, chlorine, bromine, trifluoromethyl or nitro.
Other preferred compounds of the invention are those where Ar is a substituted benzothiazole, i.e., compounds of Formula III: 
wherein
A is a covalent bond, C1-C4 alkylene group optionally substituted with C1-C2 alkyl;
X is oxygen, sulfur or NR6, wherein each R6 is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
R1, R2, R3 and R4 are each independently hydrogen, halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR7, SR7, S(O)R7, S(O)2NR7 C(O)N(R7)2 or N(R7)2, wherein each R7 is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino;
phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino; or
a group of the formula 
xe2x80x83where
J is a bond, CH2, oxygen, or nitrogen; and
each r is independently 2 or 3;
R5 is hydroxy, C1-C6 alkoxy, or xe2x80x94Oxe2x88x92M+ where M+ is a cation forming a pharmaceutically acceptable salt; and
R13, R14, R15 and R16 are independently hydrogen, halogen, nitro, hydroxy, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, trifluoromethyl, trifluoromethoxy, C1-C6 alkylsulfinyl, or C1-C6 alkylsulfonyl.
In preferred compounds of Formula III, the R13, R14, R15 and R16 substituents, in combination, represent one of bromo, cyano or nitro, one or two of fluoro, chloro, hydroxy, (C1-C6)alkyl, (C1-C6) alkoxy, or trifluoromethyl, or two fluoro or two methyl with one hydroxy or one (C1-C6)alkoxy, or one of, preferably, two fluoro and one methyl, or three fluoro groups. Particularly preferred R13, R14, R15 and R16 substituents are, independently, fluorine, chlorine, nitro, and trifluoromethyl.
In preferred compounds of Formulas II and III, A is preferably methylene, methylene substituted with a methyl group, or ethylene.
Preferred compounds according to Formula II above include those wherein R8 is fluorine, R10 is bromine and R9, R11 and R12 are hydrogens; or those wherein R8, R10, R11 and R12 are hydrogens and R9 is nitro. Other preferred compounds of Formula II include those where R2 and R3 are independently hydrogen, halogen, more preferably chloro or fluoro, C1-C6 alkyl, more preferably methyl or ethyl, alkoxy, more preferably methoxy or ethoxy, amino, mono or di(C1-C3 alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl; R8 is fluorine, R10 is bromine and R9, R11 and R12 are hydrogens; or those wherein R2 and R3 are independently hydrogen, halogen, more preferably chloro or fluoro, C1-C6 alkyl, more preferably methyl or ethyl, alkoxy, more preferably methoxy or ethoxy, amino, mono or di(C1-C3 alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl; R8 R10, R11 and R12 are hydrogens, and R9 is nitro.
Preferred compounds of Formula III above are those wherein the benzothiazole moiety is substituted with nitro, one, two, or three of fluoro, one or two of chloro, or one trifluoromethyl group. More preferred compounds of Formula II are those where A is methylene, and R5 is hydroxy or C1-C6 alkoxy. Other more preferred compounds of III are those where R2 and R3 are independently hydrogen, halogen, more preferably chloro or fluoro, C1-C6 alkyl, more preferably methyl or ethyl, alkoxy, more preferably methoxy or ethoxy, amino, mono or di(C1-C3 alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.
Still more preferred compounds of Formula III are those wherein R13, R14 and R16 are fluorines and R15 is hydrogen.
The term xe2x80x9cprodrug groupxe2x80x9d denotes a moiety that is converted in vivo into the active compound of formula I wherein R5 is hydroxy. Such groups are generally known in the art and include ester forming groups, to form an ester prodrug, such as benzyloxy, di(C1-C6)alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and (C1-C8), preferably C1-C6, more preferably C1-C3, alkoxy optionally substituted by N-morpholino and amide-forming groups such as di(C1-C6)alkylamino. Preferred prodrug groups include C1-C6 alkoxy most preferably C1-C2 alkoxy, and Oxe2x88x92M+ where M+ represents a cation. Preferred cations include sodium, potassium, ammonium, magnesium and calcium. Where M is a divalent cation such as magnesium or calcium it will be understood that such cations will be associated with more than one, generally two, carboxylate anions formed by the compound of formula I.
In certain situations, compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained as pure compounds or in enantiomeric excess, by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
Representative compounds of the present invention include the pharmaceutically acceptable acid addition salts of compounds where R5 includes basic nitrogen atom, i.e, an alkylamino or morpholino group. In addition, if the compound or prodrug of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, magnesium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
As used herein, the terms 2-benzothiazolyl and benzothiazol-2-yl are synonymous.
Representative groups of the formula 
include those where J is oxygen and each r is 2 (morpholinyl), J is nitrogen and each r is 2 (piperazinyl) or one r is 2 and the other 3 (homopiperazinyl), or J is CH2 and each r is 2 (piperidinyl) or one r is 2 and the other 3 (homopiperidinyl). Preferred groups of this formula are morpholinyl and piperazinyl. Any of these groups may optionally be substituted on a carbon atom with C1-C6 alkyl.
The heterocyclic 5-membered ring having one to three nitrogen atoms, one of which may be replaced by oxygen or sulfur includes imidazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl.
The heterocyclic 6-membered ring having one to three nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur includes triazinyl, pyrimidyl, pyridazinyl, oxazinyl and triazinyl.
The heterocyclic ring may be condensed with benzo so that said ring is attached at two neighboring carbon atoms to form a phenyl group. Such benzoheterocyclic ring may be attached to A either through the heterocyclic group or through the benzo group of the benzoheterocyclic ring. Representative examples of compounds wherein said heterocyclic ring is condensed with a benzo include benzoxazolyl, quinazolin-2-yl, 2-benzimidazolyl, quinazolin-4-yl and benzothiazolyl. The oxazole or thiazole condensed with a 6-membered aromatic group containing one or two nitrogen atoms include positional isomers such as oxazolo[4,5-b]pyridine-2-yl, thiazolo[4,5-b]pyridine-2-yl, oxazolo[4,5-c]pyridine-2-yl, thiazolo[4,5-c]pyridine-2-yl, oxazolo[5,4-b]pyridine-2-yl, thiazolo[5,4-b]pyridine-2-yl, oxazolo[5,4-c]pyridine-2-yl, and thiazolo[5,4-c]pyridine-2-yl. The 5- or 6-membered heterocyclic rings are preferably covalently bonded to the A group by a carbon atom in the heterocyclic ring, and more preferably by a carbon atom between 2 hetero atoms.
By xe2x80x9cheteroarylxe2x80x9d is meant an aromatic ring system comprising one, two or three rings of 5-, 6-, 7-, or 8-atoms per ring wherein at least one aromatic ring contains at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, isoquinolinyl, quinolinyl, napthyridinyl, benzothiazolyl, benzimidazolyl, and benzoxazolyl. Preferably, the heteroaryl group is attached to the parent molecular moiety through a carbon atom in the heteroaryl group. Where the heteroaryl group is connected to the parent moiety through a nitrogen, the adjacent X group will be an alkylene group. Preferred heteroaryl groups are monocyclic where the ring has 5 or 6 members and contains 1 or 2 nitrogen atoms, or bicyclic, where one ring has 5 or 6 members and contains 1 or 2 nitrogen atoms and the second ring has 5, 6, or 7 members and contains 0, 1, or 2 nitrogen atoms. Preferred heteroaryl groups are benzimidazolyl, imidazopyridinyl, benzothiazolyl, and imidazopyrazinyl.
The following compounds of the invention are provided to give the reader an understanding of the compounds encompassed by the invention:
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid
[5-Chloro-2-(3-trifluoromethyl-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid
[5-Chloro-2-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-phenoxy]-acetic acid
[5-Chloro-2-(3,4-dichloro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-chloro-phenoxy]-acetic acid
[4-Bromo-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-fluoro-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-methyl-phenoxy]-acetic acid
[4-nitro-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methylsulfanyl-phenoxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-4-methyl-phenoxy]-acetic acid
[2-(3-nitro-benzylcarbamdyl)-4-trifluoromethoxy-phenoxy]-acetic acid
[5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-phenoxy]-acetic acid
[5-Fluoro-2-(4-methyl-3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4,5-difluoro-phenoxy]-acetic acid
[5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-phenoxy]-acetic acid
[4-Bromo-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-4-trifluoromethoxy-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-4,5-difluoro-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid
[2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid
[2-(3-Nitro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-4-bromo-5-fluoro-phenoxy]-acetic acid
[5-(3-Nitro-benzylcarbamoyl)-2-fluoro-biphenyl-4-yloxy]-acetic acid
[5-(3-Nitro-benzylthiocarbamoyl)-2-fluoro-biphenyl-4-yloxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-4-cyano-5-fluoro-phenoxy]-acetic acid
[2-(3-Nitro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid
{5-Fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid
{5-Fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid
{5-Fluoro-2-[(5-trifluoromethyl-benzothiazol-2-ylmethyl)-carbamoyl]-phenoxy}-acetic acid
{5-Chloro-2-[(5-trifluoromethyl-benzothiazol-2-ylmethyl)-carbamoyl]-phenoxy}-acetic acid
The above compounds, further described in the Examples and other description of the invention below, are illustrative but are not meant to limit in any way the scope of the contemplated compounds according-to the present invention.
The compounds of the invention are administered to a patient or subject in need of treatment either alone or in combination with other compounds having similar or different biological activities. For example, the compounds of the invention may be administered in a combination therapy, i.e., either simultaneously in single or separate dosage forms or in separate dosage forms within hours or days of each other. Examples of such combination therapies include administering the compounds of Formula I with other agents used to treat hyperglycemia, hyperlipidemia, and diabetic complications.
Suitable compounds for use in combination therapy include
For Hyperglycemia:
Insulin
Metformin
Troglitazone
Pioglitazone
Rosiglitazone
Darglitazone
Sulfonylureass such as glipizide and glimepiride
Repaglinide
alpha-glucosidase inhibitors such as acarbose, miglitol
For Diabetic Complications:
ACE inhibitors: Captopril, lisinopril, omaprilat
Angiotensin II receptor antagonists (AT1-receptor) such as candesartan, losartan, irbesartan, and valsartan
MMP inhibitors
Protein kinase C inhibitors
For Antihyperlipidemia:
Statins such as Atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, cerivastatin
Fibrates such as Fenofibrate, bezafibrate, ciprofibrate, gemfibrozil.
Such combination therapy may involve, for example, simultaneous administration of the vasodilator, preferably an ACE inhibitor, and a compound of Formula I in separate pharmaceutical compositions, one pharmaceutical composition comprising both the vasodilator, preferably an ACE inhibitor, and the compound of Formula I, or administration of the two compounds at different times. Those skilled in the art will recognize other ways of achieving combination therapy with, for example, ACE inhibitors and the compounds of Formula I.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay, disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels on the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 1000 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be prepared by use of known chemical reactions and procedures. General methods for synthesizing the compounds are presented below. It is understood that the nature of the substituents required for the desired target compound often determines the preferred method of synthesis. All variable groups of these methods are as described in the generic description if they are not specifically defined below. More detailed procedures for particular examples are presented below in the experimental section.
In general, compounds of the invention where X in Formula I is oxygen or sulfur can be conveniently prepared from a substituted salicyclic acid using general Scheme A set forth below. 
In this method a substituted salicyclic acid moiety IV is activated and coupled with an amine. Some examples of activating methods well-known to those skilled in the art include formation of acid chlorides or mixed anhydrides and the use of coupling reagents such as 1,3-dicyclohexylcarbodiinide (DCC). A review of such methods can be found in Bodanszky, M. Principles of Peptide Synthesis; Springer-Verlag: New York, 1984. It is understood, that the choice of the coupling method used will depend on such factors as functional group compatibility and desired scale. In general, when an unprotected salicylic acid is used, formation of an acid chloride using thionyl chloride is convenient. Subsequent addition of amine V, in the presence of an amine base like triethylamine or pyridine in an aprotic solvent like dichloromethane provides amide VI. Alternatively, aqueous or biphasic reaction conditions can be used with an inorganic base such as sodium hydroxide or potassium carbonate. This reaction, known as the Schotten-Baumann reaction, is illustrated in Bioorg. Med. Chem. Letters 1994, 4, 335. Introduction of the acetic acid moiety to provide phenoxyacetic acid derivative VII is typically accomplished using an alkylating reagent like ethyl bromoacetate or sodium 2-chloroacetic acid in an aqueous acetone solution with a base such as potassium carbonate. Other method using anhydrous reaction conditions are also useful and well known to those skilled in the art of organic synthesis. If the amide product VIII is desired, ester intermediate VII can be hydrolyzed to the acid using either aqueous acid or base conditions. Thioamide derivatives X can be prepared from the corresponding amides IX by treatment with reagents like phosphorous pentasulfide in an aprotic solvent like toluene. Thioamide products X can be obtained in a manner analogue to the amide product VIII. Ester intermediate IX can be hydrolyzed to the acid using either aqueous acid or base conditions.
If the desired substituted salicylic acid is not readily available, it can be prepared using known methods. One useful method is outlined in scheme B where a 2-flourobenzoic acid XI is treated with a base like sodium hydroxide in 1,3-dimethyl-2-imidazolidinone (DMI) at elevated temperatures (preferably about 135xc2x0 C.). 
In general, the intermediate compounds IV wherein one of R1-4 is aryl or heteroaryl can be synthesized using well established transition metal catalyzed coupling reactions like the Suzuki and Stille reactions. It is understood that, depending on the specific chemistry used, a protecting group, P, may be required. The use of these general methods is illustrated in Protective Groups in Organic Synthesis, Second Edition, T. W. Green and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
In the Suzuki reaction, as outlined in scheme C, an optionally substituted aryl halide XII can be treated with an aryl- or heteroarylboronic acid and a palladium catalyst to provide the substituted salicylic acid derivatives XIII. These reactions are most often carried out in a mixture of ethereal or alcohol solvents with aqueous base in the presence of a palladium catalyst, such as Pd(OAc)2, Pd(OAc)2 w/PPh3 or Pd(PPh3)4 as described in Tetrahedron Lett. 1998, 39, 4467, J. Org. Chem. 1999, 64, 1372 and Heterocycles 1992, 34, 1395. Deprotection, if required, can be carried out using known methods to provide intermediate XIV. A general review of Suzuki cross-couplings between boronic acids and aryl halides can be found in Miyaura, N; Suzuki, A. Chem. Rev. 1995, 95, 2457. 
In addition, the Stille reaction also serves as a general method for the regiocontrolled synthesis of substitution salicylic acid intermediates XIV, as indicated in scheme D below. In this method, the salicylic acid moiety may serve as either the organotin species or the aryl halide. The stannylsalicycilic acid derivative XV is conveniently prepared from the corresponding arylbromide Arxe2x80x94Br (XII) by treatment with hexamethylditin (HMDT) and a palladium catalyst such as Pd(PPh3)4. Subsequently, this tin intermediate can be treated with a variety of partners (i.e., vinyl/allylic halides, vinyl triflates, aryl/heteroaryl halides and acyl halides, XVI) in the presence of a Palladium catalyst to provide the desired aryl- or heteroaryl coupled salicylic acid intermediates (XIII). Conversely, a halosalicylic acid derivative (XII) can be treated with a variety of tin reagents under Stille conditions to provide the desired substituted salicylic acids (XIII). For reviews of this chemistry see: (a) Heterocycles 1988, 27, 1585, (b) Synth. Comm 1992, 22, 1627, (c) Synnlett 1993, 771, (d) Helv. Chim. Acta 1993, 76, 2356 (e) J. Org. Chem. 1994, 59, 4250 and Farina, V.; Krishnamurthy, V; Scott, W., Organic Reactions, 1998, 50, 1-652. 
Transition metal catalyzed reactions can also be used to couple aryl- or heteroaryl halides with amines, alcohols and sulfur containing compounds to form the corresponding aryl- and heteroaryl aniline, ether and thioether derivatives. A general procedure for the synthesis of intermediate compounds where one of R1-4 is xe2x80x94N(H)R, is outlined in scheme E below. Typically the aryl bromide or chloride XII is treated with a heteroatom containing intermediate XV, a base such as potassium tert-butoxide or cesium carbonate, a palladium catalyst like Pd2(dba)3 or (DPPF)PdCl2 and a ligand such as BINAP or DPPF in toluene or tetrahydrofuran at elevated temperatures, typically 50-150xc2x0 C. to produce the desired intermediate XVI. 
A more detailed description of this chemistry can be found in: (a) J. Chem. Soc., Perkin Trans. 1, 1998, 2615, (b) Acc. Chem. Res. 1998, 31, 805, (c) Tetrahedron Letters, 1997, 38, 6359.
In addition to the synthesis of substituted salicylic acid intermediates, transition metal catalyzed coupling reactions can also be used to prepare target compounds from advanced intermediates. For example, as illustrated in scheme F, treatment of the intermediate bromide XVII with an aryl or heteroaryl boronic acid or tin intermediates, R-M, using Pd-mediated coupling conditions provides the desired aryl and heteroaryl product XVIII. In general the utility of this method is determined by the ease of synthesis of advanced intermediates of type XVII and the availability of aryl and heteroaryl boronic acids and tin derivatives. 
Those having skill in the art will recognize that the starting materials and reaction conditions may be varied, the sequence of the reactions altered, and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to those skilled in the art of organic synthesis.
The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference.